F-box proteins, cell cycle and cancer

Abstract

E3 ubiquitin ligases are enzymes that confer specificity to the ubiquitin-proteasome system by directly binding the proteins that are targeted for degradation. E3s are encoded by over 650 human genes, exceeding the number of genes encoding for protein kinases. Accordingly, E3 ubiquitin ligases have been linked to the control of virtually all cellular processes. In spite of their fundamental importance, our knowledge of the biological function and mechanism of action for most E3 ubiquitin ligases is still poor. Increasing our knowledge of the biological role of ubiquitin ligases is fundamental because experimental and clinical data have shown that their abnormal functions is involved in the pathogenesis of many human cancers.

During my PhD, I have investigated the function of SCF ubiquitin ligases and elucidated the molecular mechanisms by which deregulated functions of SCF ubiquitin ligases contribute to the unchecked proliferation typical of cancer cells.

I have demonstrated that SCFβTrCP targets for proteasomal degradation the basic helix-loop-helix transcription factor DEC1. In particular, I have found that the regulated proteolysis of DEC1 controls the DNA damage checkpoint. I have shown that in response to DNA damage, DEC1 is stabilized by the USP17 deubiquitylating enzyme and that during recovery from the G2 DNA damage checkpoint DEC1 is targeted for degradation by SCFβTrCP in collaboration with Casein Kinase 1a. I have also found that the same SCF ubiquitin ligase, SCFβTrCP, is responsible for the destruction of another basic helix-loop-helix transcription factor, namely TFAP4, and demonstrated that the SCFβTrCP-mediated degradation of TFAP4 is required for G2 progression and mitotic entry. In addition, I have performed a systematic analysis of the gene expression profile of 67 F-box proteins, substrate receptor subunits of SCF ubiquitin ligases, in human primary tumors and studied the biological role of a number of F-box proteins that are found overexpressed in cancer cells.